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ABSTRACT Macrophages play an integral role in host defenses against intracellular bacterial pathogens. A remarkable plasticity allows for adaptation to the needs of the host to orchestrate versatile innate immune responses to a variety of microbial threats. Several bacterial pathogens have adapted to macrophage plasticity and modulate the classical (M1) or alternative (M2) activation bias towards a polarization state that increases fitness for intracellular survival. Here, we summarize the current understanding of the host macrophage and intracellular bacterial interface; highlighting the roles of M1/M2 polarization in host defense and the mechanisms employed by several important intracellular pathogens to modulate macrophage polarization to favor persistence or proliferation. Understanding macrophage polarization in the context of disease caused by different bacterial pathogens is important for the identification of targets for therapeutic intervention. We summarize the roles of M1/M2 polarization in host defense and the mechanisms employed by several important intracellular pathogens to modulate macrophage polarization to favor persistence or proliferation.

We investigate the impact of the 2008–2009 sudden stratospheric warming (SSW) event on the mesosphere, thermosphere, and ionosphere under conditions of doubled carbon dioxide (CO2). Using the Specified Dynamics Whole Atmosphere Community Climate Model with thermosphere‐ionosphere eXtension model, we perform two simulations for the 2008–2009 SSW event—a control run and a run with 2 × CO2 concentration. Our results indicate that the zonal mean response of the upper atmosphere to the SSW is substantially modulated by 2 × CO2. During the SSW, the migrating solar semidiurnal tide (SW2) shows a ∼20% change in the lower thermosphere at around 2 × 10−5 hPa (∼115 km) under 2 × CO2 relative to the control. SSW‐driven variations in thermospheric O/N2 is modified up to ∼3% under the 2 × CO2 case. In the ionosphere, SSW‐related reduction in zonal mean electron density in the control run at equatorial and low latitudes is further modulated up to ∼8% under 2 × CO2 conditions.

Direct laser acceleration has proven to be an efficient source of high-charge electron bunches and high brilliance x-rays. However, an analytical description of the acceleration in the interaction with varying plasma density targets is still missing. Here, we provide an analytical estimate of the maximum energies that electrons can achieve in such a case. We demonstrate that the maximum energy depends on the local electron properties at the moment when the electron fulfills the resonant condition at the beginning of the acceleration. This knowledge enables density shaping for various purposes. One application is to decrease the required acceleration distance needed to achieve the maximum electron energy. Another use for density tailoring is to achieve acceleration beyond the radiation reaction limit. We derive the energy scaling law that is valid for arbitrary density profile that varies slowly compared with the betatron period. Our results can be applied to electron heating in exponential preplasma of thin foils, ablating plasma plumes, or gas jets with long-scale ramp-up.

By eliciting lung necrosis, which enhances aerosol transmission, Mycobacterium tuberculosis ( Mtb ) sustains its long-term survival as a human pathogen. In studying the human-like necrotic granuloma lesions characteristic of Mtb -infected B6.Sst1S mice, we found that lung myeloid cells display elevated senescence markers: cell cycle arrest proteins p21 and p16, the DNA damage marker γH2A.X, senescence-associated β-galactosidase activity, and senescence-associated secretory phenotype (SASP). These markers were also elevated in Mtb -infected aged wild type (WT) mice but not in young WT mice. Global transcriptomics data revealed upregulation of pro-survival (PI3K, MAPK) and anti-apoptotic pathways in Mtb -infected B6.Sst1S macrophages. As senescent cells are terminally growth-arrested yet metabolically active cells that release tissue-damaging, immunosuppressive SASP, we treated Mtb -infected mice with a cocktail of three senolytic drugs (dasatinib, quercetin, and fisetin) designed to kill senescent cells. Adjunctive senolytic drug treatment in presence of anti-tuberculosis (TB) therapy prolonged survival and reduced Mtb lung counts in B6.Sst1S and aged WT mice to a greater degree than young WT mice and concomitantly reduced lung pathology and senescence markers. These findings indicate that (1) Mtb infection induce lung myeloid cells to enter a senescent state and that these cells may promote disease progression, and (2) senolytic drugs merit consideration for human clinical trials against TB. Infection with Mycobacterium tuberculosis can induce lung necrosis. Here, Shee et al. describe a build-up of senescent cells in infected mouse lungs, and show that adjunctive treatment with host-directed senolytic drugs enhances the efficacy of anti-tuberculosis therapy in mice

Tuberculosis (TB) kills an estimated 1.25 million people annually and is the leading cause of death in people with HIV (PWH) (1). The CD4 + T helper (Th) populations play significant roles in protective immunity to Mycobacterium tuberculosis (Mtb) and are essential hosts for HIV pathogenesis. Emerging evidence in blood and gastrointestinal mucosa of PWH suggests that, among Th cells, Th17 and Th22 may be preferentially depleted during HIV infection. Targeting of Th17 and Th22 cells by HIV could pose important and poorly understood risks for Mtb containment in those with co-infection. Mtb-driven activation of Th17 and Th22 immunity may also contribute to HIV proliferation and persistence. We employed a humanized mouse model of co-infection to assess changes in Th17 and Th22 frequency and function due to infection with HIV, Mtb, or both. In infected mice, Th17 cells were the predominant host for HIV in spleen and shown to be a source of HIV replication in pulmonary TB granulomas. Th17 cells were increased in lung of mice with TB or TB-HIV. Conversely, Th22 cells were reduced in mice with HIV or TB-HIV. Mtb infection increased the viral load in lungs of co-infected mice while HIV suppressed the pulmonary Th17 family cytokine response to Mtb including IL-6, IL-22, IL-23, and IL-1β. Differential transcriptome assessment demonstrated that HIV co-infection disrupted Th17 pathways activated by Mtb in lung. Overall, these results suggest that HIV may compromise Th22 immunity and exploit Th17 cells to promote viral pathogenesis in the setting of Mtb and HIV co-infection.

The relationship between the climate and societal transformation in Maya lowlands has long been debated, particularly the role of drought in shaping the civilization trajectory during the Classic Period. A high‐resolution, multi‐proxy, geochemical record from Lake Kaná, located in the underexplored Uaymil region of the Yucatán Peninsula in Mexico, helped to reconstruct the dynamics of detrital input, redox condition, organic productivity, and carbonate precipitation over the past 2800 cal. years. Principal component analysis (PCA) of selected elements and their ratios integrated the responses to hydroclimate dynamics by yielding two rainfall‐sensitive indices, that is a focused Rainfall Index (from Al/Sr, Ti/Sr, and −Sr/Ca) and a broader element‐based Rainfall Index, for the effective and meteoric rainfalls, respectively. This new record revealed diminished detrital flux, enhanced redox stratification and low‐carbonate precipitation around 1652, 1200–900 and 600–540 cal. a BP, suggesting drought episodes and more water column anoxia. Inorganic carbon content below 5% in most of the sequence, notably, a rare condition in karstic lakes, likely resulted from sustained redox environment, siliciclastic dilution and clay‐mediated inhibition of calcite nucleation. Our results also indicated human activities between 1600–1200 cal. a BP, but of low influence. Both the climatic and anthropogenic responses captured here contribute to the growing evidence of complex climate‐society interactions across Mesoamerica and highlight the importance of an integrated geochemical approach in neotropical palaeoenvironmental reconstructions.

Consideration of soil as a living ecosystem offers the potential for innovative and sustainable solutions to geotechnical problems. This is a new paradigm for many in geotechnical engineering. Realising the potential of this paradigm requires a multidisciplinary approach that embraces biology and geochemistry to develop techniques for beneficial ground modification. This paper assesses the progress, opportunities, and challenges in this emerging field. Biomediated geochemical processes, which consist of a geochemical reaction regulated by subsurface microbiology, currently being explored include mineral precipitation, gas generation, biofilm formation and biopolymer generation. For each of these processes, subsurface microbial processes are employed to create an environment conducive to the desired geochemical reactions among the minerals, organic matter, pore fluids, and gases that constitute soil. Geotechnical applications currently being explored include cementation of sands to enhance bearing capacity and liquefaction resistance, sequestration of carbon, soil erosion control, groundwater flow control, and remediation of soil and groundwater impacted by metals and radionuclides. Challenges in biomediated ground modification include upscaling processes from the laboratory to the field, in situ monitoring of reactions, reaction products and properties, developing integrated biogeochemical and geotechnical models, management of treatment by-products, establishing the durability and longevity/reversibility of the process, and education of engineers and researchers.

Mycobacterium tuberculosis (Mtb) and HIV are leading infectious causes of death worldwide and act synergistically to worsen disease during co-infection. C-type lectin receptors (CLR) respond to pathogen-associated carbohydrates to activate downstream innate immunity and can be exploited for entry of intracellular pathogens. The macrophage (MΦ) galactose-type lectin (MGL, CLEC10A) is an immunomodulatory CLR associated with M2 MΦ. We previously described an immune role for a murine MGL homologue in an experimental model of tuberculosis (TB). Herein we extend these findings by identifying human MGL as an important member of the Mtb-responsive pathogen recognition receptor (PRR) repertoire that is activated in both M1 and M2 polarizing conditions. MΦ exposure to Mtb activates MGL expression and abundant MGL+ cells are present in TB granulomas of human lung and lymph node. Silencing of MGL permits greater Mtb replication in MΦ derived from human peripheral blood monocytes. Compared to healthy controls, MΦ and neutrophils of people with HIV (PWH) have reduced MGL and tissue MGL levels negatively correlate with viral load. Binding assays with recombinant MGL demonstrates direct interaction with Mtb, but not HIV. In vitro Mtb exposure of PBMC from PWH revealed potential recovery of the MGL defect as well as a differential activation of MGL compared to the DC-SIGN and MR CLRs. MGL is thus an important mechanism of innate immunity and potential target for host directed therapy in those with TB or TB-HIV.

The investigation of novel nanoparticles with antimicrobial activity has grown in recent years due to the increased incidence of nosocomial infections occurring during hospitalization and food poisoning derived from foodborne pathogens. Antimicrobial agents are necessary in various fields in which biological contamination occurs. For example, in food packaging they are used to control food contamination by microbes, in the medical field the microbial agents are important for reducing the risk of contamination in invasive and routine interventions, and in the textile industry, they can limit the growth of microorganisms due to sweat. The combination of nanotechnology with materials that have an intrinsic antimicrobial activity can result in the development of novel antimicrobial substances. Specifically, metal-based nanoparticles have attracted much interest due to their broad effectiveness against pathogenic microorganisms due to their high surface area and high reactivity. The aim of this review was to explore the state-of-the-art in metal-based nanoparticles, focusing on their synthesis methods, types, and their antimicrobial action. Different techniques used to synthesize metal-based nanoparticles were discussed, including chemical and physical methods and “green synthesis” methods that are free of chemical agents. Although the most studied nanoparticles with antimicrobial properties are metallic or metal-oxide nanoparticles, other types of nanoparticles, such as superparamagnetic iron-oxide nanoparticles and silica-releasing systems also exhibit antimicrobial properties. Finally, since the quantification and understanding of the antimicrobial action of metal-based nanoparticles are key topics, several methods for evaluating in vitro antimicrobial activity and the most common antimicrobial mechanisms (e.g., cell damage and changes in the expression of metabolic genes) were discussed in this review.

I analyze damage from hurricane strikes on the United States since 1955. Using machine learning methods to select the most important drivers for damage, I show that large errors in a hurricane's predicted landfall location result in higher damage. This relationship holds across a wide range of model specifications and when controlling for ex-ante uncertainty and potential endogeneity. Using a counterfactual exercise I find that the cumulative reduction in damage from forecast improvements since 1970 is about $82 billion, which exceeds the U.S. government's spending on the forecasts and private willingness to pay for them.